Strong inhibitors of COX-1 Universal cross-reactions between these NSAIDs occur At high concentration, inhibit COX-2	Poor inhibitors of COX-1 At high concentrations minimal inhibition of COX-1, without inhibition of COX-2	Preferentially inhibit COX-2 at lower doses but partially inhibit COX-1 at higher doses	Selective COX-2 inhibitors Preferentially inhibit COX-2 at prescribed doses, no inhibition of COX-1 occur
Acetylsalicylic acid (Aspirin) Ibuprofen Naproxen Ketorolac Indomethacin Etodolac Diclofenac Piroxicam Sulindac Tolmetin Fenoprofen Oxaprozin Mefanamic acid Flurbiprofen Difluinisal Ketoprofen Nabumetone	Acetaminophen (paracetamol) Relatively safe alternative for almost all patients with AERD High doses (≥1000 mg) have been reported to provoke easily reversed bronchospasm in some with AERD Salsalate	Nimesulide Meloxicam (≥15 mg)	Available in US Celecoxib Not available in US Etoricoxib Parecoxib Lumiracoxib Pulled from US market Rofecoxib Valdecoxib

Aspirin-Exacerbated Respiratory Disease (AERD)

Definition

Affects up to 0.9% of general population, up to 20% of asthmatics, and up to 40% of asthmatics with nasal polyps
Onset: teenage years - middle adulthood

AERD Triad
--1-	Chronic sinusitis with nasal polyps	Nasal congestion with anosmia that progresses to chronic hypertrophic eosinophilic pansinusitis with polyps Polyps regrow rapidly after surgery
--2	Asthma	May precede the sinus disease or occur later
--3	Sensitivity to any medication that inhibits COX-1	See COX-1 inhibitors table below Acute ingestion of ASA and most NSAIDs results in upper and/or lower respiratory reactions including rhinitis, conjunctivitis, laryngospasm and bronchospasm

Diagnosis of AERD

History of respiratory symptom exacerbation following ASA or NSAID dose is suggestive
- Borish: diagnosis is best supported by a compelling history of upper and/or lower respiratory compromise in response to ASA/NSAIDs occurring on 2 separate occasion
  - ASA/NSAID-induced exacerbations of GERD may trigger upper and lower airways symptoms in the absence of AERD
  - ASA/NSAID-induced urticaria/angioedema is emphatically not associated with AERD
- Alcohol ingestion causes respiratory reactions in the majority of patients with AERD (typically within 3 glasses and/or 1 hour)

Aspirin challenge is the gold standard for diagnosing AERD
- Challenge may be performed via oral route (common in US), bronchial inhalation, nasal inhalation (Europe) and IV
- Diagnosis of aspirin-exacerbated cutaneous disease is based on history; these patients should not undergo challenges with the suspected drugs and should be considered cross-reactors (or multiple reactors), even if they have histories of urticaria induced by a single NSAID
CT or plain radiographs of the sinuses reveal complete opacification in nearly all AERD patients; normal imaging of the sinuses essentially rules out AERD
Peripheral eosinophilia (when off systemic steroids) is a cardinal feature of AERD, and a patient without this lab finding does not have AERD
Urinary leukotriene E4 (LTE4) - more likely to be elevated in AERD, and higher baseline LTE4 values increase risk of reaction during oral ASA challenges. However, urine LTE4 is not diagnostic as many AERD patients have low values.

Treatment of AERD

Overall approach (Borish): medical polypectomy (steroid taper x 21 days), followed by maintenance with budesonide/saline sinus rinses, followed by surgical polypectomy if this not effective
Anti-leukotriene medications: montelukast may be helpful but zileuton may be especially effective (shown to shrink polyps, improve sinus/asthma symptoms, restore sense of smell in 50%)
Aspirin desensitization and daily treatment with aspirin - significantly improves overall symptoms and quality of life, decreases formation of nasal polyps and sinus infections, reduces the need for oral steroids and sinus surgery, and improves nasal and asthma scores in patients with AERD
- Surgical polypectomy 2-4 weeks before desensitization is ideal because desensitization is most effective in preventing new polyp formation, and procedure may be safer because there is less polyp tissue to produce inflammatory mediators
- If desensitization not performed, patients must completely avoid COX-1 inhibitors. Even with strict avoidance, most AERD patients develop progressively worsening airway disease
- Aggressive medical management must be continued after surgery and aspirin desensitization (e.g. zileuton and budesonide nasal saline rinses) to retard polyp regrowth

ASA Challenge and Desensitization Protocol (Scripps Clinic)

Indications	Typical indications Intractable symptoms despite medical treatment Recurrent nasal polyps requiring multiple surgeries Frequent or daily systemic corticosteroids are required to control nasal symptoms and/or asthma Additional medical indication for aspirin (e.g. antiplatelet therapy for cardiovascular diseases, arthritis) Obtain signed informed consents prior to challenge and desensitization
Contraindications	Unstable asthma Patient should have FEV1 ≥1.5L, >60% predicted, and within 10% of best prior value Pregnancy Gastric ulcers Bleeding disorders
Pretreatment	Start montelukast 10 mg PO QD 2-4 weeks prior to challenge (if not already taking it) Stabilize asthma and treat all other concomitant conditions that may affect safety, tolerability, and efficacy of desensitization Asthma, AR - oral steroids if necessary, continue all of patient's current medications for upper and lower airways, including inhaled/intranasal steroids Polyps - debulking nasal polyposis 2-4 weeks before desensitization is ideal because desensitization most effective in preventing new polyp formation, and procedure may be safer because there is less polyp tissue to produce inflammatory mediators GERD - consider PPI, H2 blocker, fundoplication if severe Infections (sinus, pulmonary)
Discontinue medications	Stop antihistamines and decongestants 48 hours prior Stop SABA on day of challenge

	Oral aspirin challenge Standard method in US	Intranasal ketorolac and modified oral aspirin challenge Preferred method at Scripps Clinic Faster with decreased risk of laryngospasm and GI adverse effects Contraindicated if nasal obstruction due to polyps (but best candidates for ASA desensitization have recent surgical polypectomy)
Prepare challenge materials	ASA 81 mg tablets cut with a pill cutter into fourths, halfs, etc	ASA 81 mg tablets cut with a pill cutter into fourths, halves, etc Prepare intranasal ketorolac Mix 2 mL of ketorolac tromethamine IV solution (60 mg/2 mL) and 2.75 mL preservative free normal saline in an empty nasal spray bottle that delivers 100 microliters/actuation (e.g. Nasocort AQ bottle) Prime with 5 sprays before use; each 0.1 mL spray = 1.26 mg of ketorolac Tilt head down while spraying and sniff gently to avoid swallowing Sprix (ketorolac nasal spray) approved by FDA and may be useful
Choose challenge setting	Safe to perform in outpatient setting Inpatient desensitization should be strongly considered in patients receiving beta-blockers, recent myocardial infarction, and/or with severe/uncontrolled asthma
Placebo challenge day	A placebo challenge can be conducted the week before Alternatively, if the patient’s baseline FEV1 is the same as their prior best value and they have not used their albuterol rescue inhaler in the past week, you can skip the placebo challenge
Day 1	FEV1 every hour, wait 3 hours between doses Challenge dosing Q3 hours: 8 AM: 20-40 mg PO 11 AM: 40-60 mg PO 2 PM: 60-100 mg PO 5 PM: discharge Most reactions occur at 45-100 mg Choose lower dose if the patient is not using a leukotriene-modifying drug, has a low baseline FEV1, and/or has had a recent hospitalization or ED visit for asthma	Clinical and objective evaluation with spirometry performed before each dose and PRN Challenge dosing: 8 AM: 1 spray (in one nostril) 8:30 AM: 2 sprays (1 in each nostril) 9 AM: 4 sprays (2 in each nostril) 9:30 AM: 6 sprays (3 in each nostril) 10:30 AM: 60 mg PO 12 PM: 60 mg PO 3 PM: discharge
Day 2	Measure FEV1 every hour and wait 3 hours between doses Challenge dosing Q3 hours: 8 AM: 100-160 mg PO 11 AM: 160-325 mg PO 2 PM: 325 mg PO 5 PM: discharge	Challenge dosing: 8 AM: 150 mg PO 11 AM: 325 mg PO 2 PM: discharge
Criteria for positive challenge	Positive challenge if any of the following occur: Naso-ocular symptoms Classic reaction - Naso-ocular symptoms and a ≥15% decline in FEV1 Lower respiratory reaction only - FEV1 declines by >20% Laryngospasm (flat or notched inspiratory curve) with or without other symptoms Systemic reaction: hives, flush, gastric pain, hypotension Manage reactions If reaction occurs in larynx or bronchi, treat, wait for resolution, repeat provoking dose, and continue dose escalation Q3 hours Bronchospam - SABA Laryngeal reaction - racemic epinephrine, IM epinephrine If reaction isolated to eyes/nose, may treat, and continue to next scheduled dose Naso-ocular - oxymetazoline nasal spray (e.g. Afrin), PO/topical antihistamines Cutaneous reactions (flushing, urticaria, angioedema) - antihistamines PO/IV Gastric symptoms (nausea, vomiting and abdominal cramping pain) - PO/IV H2-antihistamines Systemic reactions - IVF and IM epinephrine available but rarely needed (0.002%) If positive challenge occur may proceed to desensitization
Criteria for negative challenge	Negative challenge if no reaction occurs 3 hours after ASA 325 mg given If patient has not reacted to 325 mg of ASA, they will not react to 650 mg Some consider proceeding with ASA desensitization therapy for a 1 month trial even if there is a negative challenge due to the possibility that a positive challenge was masked by montelukast
Desensitization	After positive challenge symptoms are treated/resolved, repeat provoking dose (same dose that caused positive challenge) If no reaction seen with repeat dose, continue to escalate until dose of 325 mg PO reached Once 325 mg PO is tolerated, desensitization is complete: give ASA 650 mg PO as first dose and continue at 650 mg PO BID for at least 1 month
Follow-up	Titrate aspirin dose If there is significant improvement after 650 mg PO BID x 1 month, decrease by one tablet (325 mg) each month to 650 mg PO QAM and 325 mg PO QHS, and then ideally decrease again to 325 mg PO BID Titrate dose of ASA down to lowest effective dose (usually 325 mg PO BID) A dose as low as 81 mg PO QD can maintain the desensitized state, which may be sufficient for patients who need only cardiovascular prophylaxis, but is usually suboptimal for treating AERD which requires at least 325 mg PO QD Manage common side effects GERD/ulcer prophylaxis Treat aspirin-induced urticaria with antihistamines A case series suggests that dose-dependent pancreatitis (easily misdiagnosed as gastritis) may occur Interruption of therapy If there are brief interruptions (<48 hours) due to surgery or illness, aspirin may be restarted at previous dose due to a desensitized refractory period (24-72 hours) If >48 hour interruption, recommend repeat desensitization Pregnancy - due to risk of adverse effects on fetus with NSAID use during pregnancy, it may be prudent to discontinue NSAID use then desensitize again after pregnancy

Practice Parameter (2010)

Approach to Patients with Cardiovascular Disease and ASA Hypersensitivity

Background

True IgE-mediated reactions to ASA seem to be non-existent or very rare
The goal of the allergist is to safely deliver at least ASA 81 mg (low dose) to the patient requiring this drug for its antiplatelet effect
- In the CURRENT-OASIS 7 trial, there was no significant difference between ASA 75–100 mg and 300-325 mg on cardiovascular death, MI, and stroke at 30 days
- In combination with other potent platelet inhibitors (prasugrel and clopidogrel) there are no data to suggest that ASA 325 mg is more efficacious than 81 mg at preventing restenosis in the first 24–48 hours

Protocols

Scripps Clinic

Contraindications	Contraindicated in patients with an unstable arterial lesion (evolving MI, TIA, or CVA, etc.), the intravascular intervention should occur first and considerations for challenge/desensitization should be secondary; this is due to the real possibility of causing asthma (AERD) or histamine-mediated coronary vasospasm Patients with a history of ASA/NSAID induced SJS, TEN, DRESS, allergic interstitial nephritis, serum sickness Relative contraindication for chronic urticaria/angioedema, because this condition may make long term use of ASA/NSAIDs impossible to manage
Location	A one-to-one, constant nursing attendance is required, with the supervising physician immediately available At Scripps Clinic, virtually all ASA procedures occur in the outpatient clinic, but it is "recognized that in other clinics/practices this same approach to aspirin challenge/desensitization will be undertaken in a monitored hospital bed"
Pretreatment	Patients without AERD If the patient is unstable enough that continued hospitalization is required for management of the underlying condition, then premedication with steroids, antihistamines, and montelukast is acceptable even if it prevents diagnosis of hypersensitivity by masking the reaction If the patient is seen as an outpatient, then avoidance of pretreatment is strongly recommended on order to obtain an accurate diagnosis Patients with AERD Montelukast 10 mg, ICS/LABA, systemic corticosteroids ("usually IV"), and antihistamines Obtain baseline spirometry
Dosing	If convincing history of a particularly severe reaction, start with ASA 20.25 mg (1/4 81 mg baby ASA tablet cut with a pill cutter), wait 90 min, repeat 20.25 mg, wait 90 min, then give 40.5 mg, then wait 90 min For other patients, start with ASA 40.5 mg, wait 90 min, then repeat 40.5 mg, then wait 90 min AERD patients most likely will react after the second 40.5 mg dose Discharge patient, who may begin ASA 81 mg PO QD treatment the next day If higher doses are desired by the referring cardiologist, patient may return the next day for additional updosing (start with ASA 121.5 mg, wait 90 min, 202.5 mg, wait 90 min, 325 mg, wait 3 hours)